This application is for a Program Project focusing on the molecular basis for idiopathic dry mouth. The clinical entity of xerostomia or dry mouth afflicts about 3 million Americans leading to a variety of symptoms and consequences of potentially high morbidity. The impairment of salivary function comprises the sensation of oral dryness, difficulties in speech, mastication and deglutition, increased susceptibilities to oral microbial diseases such as caries and fungal infections, and reduced protection of tooth mineral. Well established causes for salivary hypofunction are side effects of medications, damage to salivary gland tissue by radiation therapy or autoimmune diseases such as Sjogren's syndrome. There is, however, a subset of xerostomic patients comprising about 20% of all dry mouth patients for whom no obvious etiology can be ascertained and these patients are therefore diagnosed with "idiopathic dry mouth". The presence or absence of objective parameters for salivary flow allows a further subdivision of idiopathic dry mouth patients. Since the underlying mechanisms for idiopathic dry mouth have not been established the therapeutic approaches available so far are only palliative at best. The studies outlined in this proposal are designed to gain fundamental knowledge at the molecular level in this area of exocrine biology. The data to be generated by the proposed studies have the ultimate goal to open new avenues for therapeutic applications. The overall aims of this Program Project is to determine the mechanisms responsible for idiopathic forms of dry mouth. There are 3 subprojects aimed at testing separate but interrelated hypotheses of salivary dysfunction.